Effects of statins on proinflammatory/prothrombotic biomarkers and on disease activity scores in SLE patients: data from LUMINA (LXXVI), a multi-ethnic US cohort.

OBJECTIVES: We sought to determine the effect of statin therapy on the levels of proinflammatory/prothrombotic markers and disease activity scores in patients with SLE in a multi-ethnic, multi-centre cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients placed on statins (n=21) therapy taken before and after at least 6 months of treatment were tested. Disease activity was assessed using SLAM-R scores. Interleukin (IL)-1ß, IL-6, IL-8, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and anticardiolipin (aCL) antibodies were evaluated using ELISA assays while high sensitivity C-reactive protein (hsCRP) was assessed by nephelometry. Plasma/serum samples from frequency- matched healthy donors were used as controls. RESULTS: Levels of IL-6, VEGF, sCD40L and TNF-α were significantly elevated in SLE patients versus controls. Statin therapy resulted in a significant decrease in SLAM-R scores (p=0.0199) but no significant changes in biomarker levels were observed. There was no significant association of biomarkers with SLAM-R scores. CONCLUSIONS: Statin therapy resulted in significant clinical improvement in SLE patients, underscoring the use of statins in the treatment of SLE.

Evaluation of different immunoassays for the detection of antiphospholipid antibodies: report of a wet workshop during the 13th International Congress on Antiphospholipid Antibodies.

BACKGROUND: The performance and standardization of anticardiolipin (aCL) and anti-ß2 glycoprotein I antibodies (aß2GPI) tests for the confirmation of diagnosis of antiphospholipid syndrome (APS) remain a matter of debate and concern. We evaluated the performance of different ELISAs and other new immunoassays for the detection of aCL and aß2GPI in a wet workshop at the 13th International Congress on Antiphospholipid Antibodies in Galveston, TX (April 13th, 2010, APLA 2010). METHODS: Aliquots of 26 un-identified APS or persistently aPL positive serum samples and 21 controls (9 from healthy individuals and 5 from patients with infectious diseases and 7 with various autoimmune diseases) were distributed to all participants/groups. All serum samples were evaluated in various aCL and aß2GPI ELISAs, a chemiluminescent immunoassay, a fluoro-enzyme immunoassay, and in a multiplexed immunoassay system. Monoclonal and polyclonal calibrators were also evaluated. RESULTS: Although not all the assays reported the titers of aCL and aß2GPI in the same units, the correlation of positive titers among the assays was good. All aCL and aß2GPI tests showed excellent clinical sensitivities, specificities and positive predictive values and good agreement with respect to the levels of the IgG and IgM antibodies, regardless of assay type, or whether tests were done using automated or "manual" systems. CONCLUSIONS: New methodologies for the detection of aPL look promising and comparable to currently approved ELISA tests. This study provides evidence of progress of efforts of harmonization of tests used to detect aPL.

C6 knock-out mice are protected from thrombophilia mediated by antiphospholipid antibodies.

BACKGROUND: Complement activation plays a role in pathogenesis of the antiphospholipid syndrome (APS), but the involvement of the C5b-9 membrane attack complex (MAC) is unknown. Here we studied the effects of human polyclonal antiphospholipid (aPL) antibodies on thrombosis and tissue factor (TF) up-regulation in C6 deficient (C6(-/-)) mice. METHODS: C6(-/-) mice or the wild-type C3H/HeJ (C6(+/+)) mice were injected twice with IgG-APS (n = 2) or IgM-APS (n = 1) isolated from APS patients or with the corresponding control immunoglobulins (Igs) of normal human serum, (NHS) (IgG-NHS or IgM-NHS). Then, the sizes of induced thrombi in the femoral vein were determined 72 hours after the first injection. Tissue factor was determined in homogenates of carotid arteries and in peritoneal macrophages. RESULTS: Thrombus sizes were significantly larger in C6(+/+) treated with IgG-APS1 or with IgG-APS2 or with IgM-APS when compared with C6(+/+) mice treated with IgG-NHS or with IgM-NHS, respectively. The sizes of thrombi were significantly smaller in the C6(-/-) mice injected with IgG-APS1, IgG-APS2 or IgM-APS (p < 0.001), compared to their C6(+/+) counterparts showing an important abrogation of thrombus formation in mice lacking C6. The TF expression and activity in the C6(-/-) mice treated with IgG-APS or IgM-APS were diminished when compared to C3H/HeJ (C6(+/+)) mice treated with the same Igs. All mice injected with IgG-APS and IgM-APS had medium-high titers of anticardiolipin (aCL) and anti-ß(2)glycoprotein I (aß(2)GPI) antibodies. CONCLUSIONS: These data indicate that the C6 component of the complement system mediates aPL-thrombogenic effects, underscoring an important pathogenic mechanism and indicating the possibility of inhibiting complement to ameliorate APS-related manifestations.

Effect of hydroxychloroquine treatment on pro-inflammatory cytokines and disease activity in SLE patients: data from LUMINA (LXXV), a multiethnic US cohort.

OBJECTIVE: We sought to determine the effect of hydroxychloroquine therapy on the levels proinflammatory/prothrombotic markers and disease activity scores in patients with systemic lupus erythematosus (SLE) in a multiethnic, multi-center cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients (n = 35) were evaluated at baseline and after hydroxychloroquine treatment. Disease activity was assessed using SLAM-R scores. Interferon (IFN)-α2, interleukin (IL)-1ß, IL-6, IL-8, inducible protein (IP)-10, monocyte chemotactic protein-1, tumor necrosis factor (TNF)-α and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Anticardiolipin antibodies were evaluated using ELISA assays. Thirty-two frequency-matched plasma/serum samples from healthy donors were used as controls. RESULTS: Levels of IL-6, IP-10, sCD40L, IFN-α and TNF-α were significantly elevated in SLE patients versus controls. There was a positive but moderate correlation between SLAM-R scores at baseline and levels of IFN-α (p = 0.0546). Hydroxychloroquine therapy resulted in a significant decrease in SLAM-R scores (p = 0.0157), and the decrease in SLAM-R after hydroxychloroquine therapy strongly correlated with decreases in IFN-α (p = 0.0087). CONCLUSIONS: Hydroxychloroquine therapy resulted in significant clinical improvement in SLE patients, which strongly correlated with reductions in IFN-α levels. This indicates an important role for the inhibition of endogenous TLR activation in the action of hydroxychloroquine in SLE and provides additional evidence for the importance of type I interferons in the pathogenesis of SLE. This study underscores the use of hydroxychloroquine in the treatment of SLE.

Maesopsin 4-O-beta-D-glucoside, a natural compound isolated from the leaves of Artocarpus tonkinensis, inhibits proliferation and up-regulates HMOX1, SRXN1 and BCAS3 in acute myeloid leukemia.

The leaves of Artocarpus tonkinensis are used in Vietnamese traditional medicine for treatment of arthritis, and the compound maesopsin 4-O-ß-D-glucoside (TAT-2), isolated from them, inhibits the proliferation of activated T cells. Our goal was to test the anti-proliferative activity of TAT-2 on the T-cell leukemia, Jurkat, and on the acute myeloid leukemia, OCI-AML. TAT-2 inhibited the growth of OCI-AML (and additional acute myeloid leukemia cells) but not Jurkat cells. Growth inhibition was shown to be due to inhibition of proliferation rather than increase in cell death. Analysis of cytokine release showed that TAT-2 stimulated the release of TGF-ß, yet TGF-ß neutralization did not reverse the maesopsin-dependent effect. Gene expression profiling determined that maesopsin modulated 19 identifiable genes. Transcription factor CP2 was the gene most significantly modulated. Real-time PCR validated that up-regulation of sulphiredoxin 1 homolog (SRXN1), hemeoxygenase 1 (HMOX1), and breast carcinoma amplified sequence 3 (BCAS3) were consistently modulated.

'Criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, Texas, April 2010.

Current classification criteria for definite antiphospholipid syndrome (APS) mandate the use of one or more of three positive 'standardized' laboratory assays to detect antiphospholipid antibodies (aPL) (viz: anticardiolipin [aCL] IgG and IgM; anti-ß(2)glycoprotein I [anti-ß(2)GPI] antibodies IgG and IgM; and/or a lupus anticoagulant [LAC]), when at least one of the two major clinical manifestations (thrombosis or pregnancy losses) are present. Although, efforts of standardization for these 'criteria' aPL tests have been conducted over the last 27 years, reports of inconsistencies, inter-assay and inter-laboratory variation in the results of aCL, LAC, and anti-ß(2)GPI, and problems with the interpretation and the clinical value of the tests still exist, which affect the consistency of the diagnosis of APS. A Task Force of scientists and pioneers in the field from different countries, subdivided in three working groups, discussed and analyzed critical questions related to 'criteria' aPL tests in an evidence-based manner, during the 13(th) International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX). These included: review of the standardization and the need for international consensus protocol for aCL and anti-ß(2)GPI tests; the use of monoclonal and/or polyclonal standards in the calibration curve of those tests; and the need for establishment of international units of measurement for anti-ß(2)GPI tests. The group also reviewed the recently updated guidelines for LAC testing, and analyzed and discussed the possibility of stratification of 'criteria' aPL tests as risk factors for APS, as well as the clinical value of single positive vs. multiple aPL positivity. The group members presented, discussed, analyzed data, updated and re-defined those critical questions at a preconference workshop that was open to congress attendees. This report summarizes the findings, conclusions, and recommendations of this Task Force.

'Non-criteria' aPL tests: report of a task force and preconference workshop at the 13th International Congress on Antiphospholipid Antibodies, Galveston, TX, USA, April 2010.

Abstract: Current classification criteria for definite APS recommend the use of one or more of three positive standardized laboratory assays, including anticardiolipin antibodies (aCL), lupus anticoagulant (LA), and antibodies directed to ß(2)glycoprotein I (anti-ß(2)GPI) to detect antiphospholipid antibodies (aPL) in the presence of at least one of the two major clinical manifestations (i.e., thrombosis or pregnancy morbidity) of the syndrome. Several other autoantibodies shown to be directed to phospholipids and/or their complexes with phospholipids and/or to proteins of the coagulation cascade, as well as a mechanistic test for resistance to annexin A5 anticoagulant activity, have been proposed to be relevant to APS. A task force of worldwide scientists in the field discussed and analyzed critical questions related to 'non-criteria' aPL tests in an evidence-based manner during the 13th International Congress on Antiphospholipid Antibodies (APLA 2010, 13-16 April 2010, Galveston, Texas, USA). This report summarizes the findings, conclusions, and recommendations of this task force.

Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies.

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-ß2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Antiphospholipid Syndrome Clinical Research Task Force report.

The Antiphospholipid Syndrome (APS) Clinical Research Task Force (CRTF) was one of six Task Forces developed by the 13(th) International Congress on Antiphospholipid Antibodies (aPL) organization committee with the purpose of: a) evaluating the limitations of APS clinical research and developing guidelines for researchers to help improve the quality of APS research; and b) prioritizing the ideas for a well-designed multicenter clinical trial and discussing the pragmatics of getting such a trial done. Following a systematic working algorithm, the Task Force identified five major issues that impede APS clinical research and the ability to develop evidence-based recommendations for the management of aPL-positive patients: (1) aPL detection has been based on partially or non-standardized tests, and clinical (and basic) APS research studies have included patients with heterogeneous aPL profiles with different clinical event risks; (2) clinical (and basic) APS research studies have included a heterogeneous group of patients with different aPL-related manifestations (some controversial); (3) thrombosis and/or pregnancy risk stratification and quantification are rarely incorporated in APS clinical research; (4) most APS clinical studies include patients with single positive aPL results and/or low-titer aPL ELISA results; furthermore, study designs are mostly retrospective and not population based, with limited number of prospective and/or controlled population studies; and (5) lack of the understanding the particular mechanisms of aPL-mediated clinical events limits the optimal clinical study design. The Task Force recommended that there is an urgent need for a truly international collaborative approach to design and conduct well-designed prospective large-scale multi-center clinical trials of patients with persistent and clinically significant aPL profiles. An international collaborative meeting to formulate a good research question using 'FINER' (Feasible; Interesting; Novel; Ethical; and Relevant) criteria took place in November 2010.

Glucocorticoid-induced activation of caspase-8 protects the glucocorticoid-induced protein Gilz from proteasomal degradation and induces its binding to SUMO-1 in murine thymocytes.

In this study, we evaluated the possible cross-talk between glucocorticoid (GC)-induced leucine zipper (Gilz) and caspase-8 in dexamethasone (Dex)-treated thymocytes. We determined that expression of Dex-induced Gilz protein was reduced when caspase-8 activity was inhibited, and this effect was not partially due to altered Gilz mRNA expression. Inhibition of the proteasome abrogated this reduction in Gilz expression, suggesting that Dex-induced caspase-8 activation protects Gilz from degradation. We hypothesized that the caspase-8-dependent protection of Gilz could be due to caspase-8-driven sumoylation. As a putative small ubiquitin-like modifier (SUMO)-binding site was identified in the Gilz sequence, we assessed whether SUMO-1 interacted with Gilz. We identified a 30-kDa protein that was compatible with the size of a Gilz-SUMO-1 complex and was recognized by the anti-SUMO-1 and anti-Gilz antibodies. In addition, Gilz bound to SUMO ubiquitin-conjugating (E2)-conjugating enzyme Ube21 (Ubc9), the specific SUMO-1 E2-conjugating enzyme, in vitro and coimmunoprecipitated with Ubc9 in vivo. Furthermore, Gilz coimmunoprecipitated with SUMO-1 both in vitro and in vivo, and this interaction depended on caspase-8 activation. This requirement for caspase-8 was further evaluated in caspase-8-deficient thymocytes and lymphocytes in which Gilz expression was reduced. In summary, our results suggest that caspase-8 activation protects Gilz from proteasomal degradation and induces its binding to SUMO-1 in GC-treated thymocytes.

Anti-phospholipid antibody mediated fetal loss: still an open question from a pathogenic point of view.

Antiphospholipid antibodies (aPL) are associated with recurrent miscarriages and pregnancy complications, however their pathogenic mechanisms are still matter of research. Thrombotic events at the placental level cannot explain all of the clinical manifestations. It has been suggested that aPL may be responsible for a local acute inflammatory response mediated by complement activation and neutrophil infiltration eventually leading to fetal loss. However histological and immunohistological studies on human placental samples do support such a mechanism only in part and with no any clear relationship with the pregnancy outcome. A direct effect of aPL on both maternal and fetal placental tissues has been reported through the reactivity of the antibodies with beta2 glycoprotein I (beta2GPI) expressed on the cell membranes. These events do not require an inflammatory response and can be in part related to the inhibition of growth factors favouring a physiological placentation. Understanding the different pathogenic mechanisms of aPL-associated miscarriages may help in improving our therapeutic approach particularly in recurrent cases not responsive to the usual treatment.

Antiphospholipid syndrome treatment beyond anticoagulation: are we there yet?

Persistently positive antiphospholipid antibodies in association with thromboses and/or pregnancy morbidity is the hallmark of the antiphospholipid syndrome. The management of antiphospholipid antibody-positive patients has been focused on utilizing anti-thrombotic medications such as heparin or warfarin. Given that our understanding of the molecular mechanisms of antiphospholipid antibody-mediated thrombosis has been growing, it is highly likely that the current 'anti-thrombotic' approach to these patients will be replaced by an 'immunomodulatory' approach in the near future. This review article will address the experimental and/or clinical evidence behind some of these potential 'immunomodulatory' approaches (tissue factor inhibition, P38 mitogen-activated protein kinase inhibition, nuclear factor-kappaB inhibition, platelet glycoprotein receptor inhibition, hydroxychloroquine, statins, inhibition of beta(2)GPI and/or anti-beta(2)GPI binding to target cells, complement inhibition, and B cell inhibition) in antiphospholipid syndrome.

Antiphospholipid syndrome: a comprehensive review of a complex and multisystemic disease.

The antiphospholipid syndrome (APS) is an acquired thombophilia, which is characterized by one or more thrombotic episodes and obstetric complications in the presence of antiphospholipid (aPL) antibodies (Abs). APL Abs are detected by laboratory tests such as lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-Beta2-glycoprotein I (Beta2GPI) Abs. This article reviews the most current aspects of APS with emphasis on the pathophysiology of the disease, clinical manifestations, laboratory tests, and current modalities of treatment.

Isolated elevation of IgA anti-beta2glycoprotein I antibodies with manifestations of antiphospholipid syndrome: a case series of five patients.

Current diagnostic classification criteria recommend elevated titres of anti-cardiolipin (aCL) and/or anti-beta(2)GPI antibody by ELISA IgG or IgM and/or lupus anticoagulant (LA) to confirm antiphospholipid syndrome (APS). Although IgA aPL antibodies have been shown to be pathogenic in animal models of APS, their clinical significance has remained elusive. We report four cases of exclusive IgA anti-beta(2)GPI antibody sero-positivity with concomitant clinical manifestations associated with APS. Four of the five patients were LA negative. 1) Thirty-eight-year-old African-American female with SLE presented with resolving digital ulcers. Serum IgA anti-beta(2)GPI antibody titres were 118.5 SAU (normal range: 0-20 SAU). 2) Twenty-seven-year-old African-American woman with SLE was evaluated for recent onset of severe headaches, unresponsive to analgesics and anti-migraine medications. MRI of the brain revealed hyper-intensities in the white matter in the frontal lobes. Serum IgA anti-beta(2)GPI antibody titres were 29.1 Standard A Units (SAU). 3) Thirty-two-year-old Hispanic female with history of two unexplained miscarriages and negative serologies for SLE. Serum IgA anti-beta(2)GPI antibody titres were 102.0 SAU. 4) Twenty-five-year-old white female with history of recent unexplained miscarriage in the 11th week of gestation and associated complaints of numbness and tingling in her hands. Her IgA anti-beta(2)GPI antibody titre was 62.0 SAU. 5) Twenty-five-year-old African-American woman with SLE, positive for anti-Ro antibodies with a history of ischemic fingers, a pregnancy loss and recent pregnancy complicated due to pre-eclampsia. Her LA was positive and her IgA anti-beta(2)GPI antibody titer was 186.0 SAU. This case series supports that elevated IgA anti-beta(2)GPI antibody titres may identify additional patients who have clinical features of APS but who do not meet current diagnostic criteria.

In vivo inhibition of antiphospholipid antibody-induced pathogenicity utilizing the antigenic target peptide domain I of beta2-glycoprotein I: proof of concept.

SUMMARY OBJECTIVES: In the antiphospholipid syndrome (APS), the immunodominant epitope for the majority of circulating pathogenic antiphospholipid antibodies (aPLs) is the N-terminal domain I (DI) of beta(2)-glycoprotein I. We have previously shown that recombinant DI inhibits the binding of aPLs in fluid phase to immobilized native antigen, and that this inhibition is greater with the DI(D8S/D9G) mutant and absent with the DI(R39S) mutant. Hence, we hypothesized that DI and DI(D8S/D9G) would inhibit aPL-induced pathogenicity in vivo. METHODS: C57BL/6 mice (n = 5, each group) were injected with purified IgG derived from APS patients (IgG-APS, 500 microg) or IgG from normal healthy serum (IgG-NHS) and either recombinant DI, DI(R39S), DI(D8S/D9G), or an irrelevant control peptide (at 10-40 microg). Outcome variables measured were femoral vein thrombus dynamics in treated and control groups following standardized vessel injury, expression of vascular cell adhesion molecule-1 (VCAM-1) on the aortic endothelial surface, and tissue factor (TF) activity in murine macrophages. RESULTS: IgG-APS significantly increased thrombus size as compared with IgG-NHS. The IgG-APS thrombus enhancement effect was abolished in mice pretreated with recombinant DI (P

Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome.

The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptive immune response against self phospholipid (PL)--binding proteins. Although APS is considered as an autoantibody-mediated disease, there is now evidence that anti-phospholipid antibodies (aPL) are necessary but not sufficient to trigger some of the clinical manifestations of the syndrome. For example, mediators of the innate immunity are recognized to be additional second hits able to induce the thrombotic events in the presence of aPL. Finally, environmental agents - in particular infectious ones - were reported to act as triggers for the production of autoantibodies cross-reacting with PL-binding proteins as well as inflammatory stimuli that potentiate the aPL thrombogenic effect. Altogether, these findings suggest a role for the innate immunity in APS pathogenesis. Toll-like receptors (TLR) are receptors that induce prompt inflammatory responses and mediate functional activation in immune effector cells. There is evidence that aPL, and in particular anti-beta(2) glycoprotein I (beta(2)GPI) antibodies, may activate endothelial cells and monocytes through TLR-4-dependent signalling. Whether or not TLR may behave as surface receptors for beta(2)GPI is still matter of research. Drugs or molecules able to interfere with TLR involvement may represent new therapeutic approaches for APS.

In vivo effects of an inhibitor of nuclear factor-kappa B on thrombogenic properties of antiphospholipid antibodies.

It has been shown that endothelial cell (EC) activation and tissue factor (TF) upregulation in EC and monocytes by antiphospholipid antibodies (aPL Abs) leads to a prothrombotic state and involves translocation of nuclear factor-kappa B (NF-kappaB). Here we examined the effects of an NF-kappaB inhibitor on aPL-induced thrombosis, TF activity, and EC in vivo. We treated CD1 mice with IgG from a patient with antiphospholipid syndrome (IgG-APS) or with control IgG (IgG-NHS). The adhesion of leukocytes (number of white blood cells) to EC in cremaster muscle (as an indication of EC activation) as well as the size of an induced thrombus in the femoral vein of the mice were examined. Some mice in each group were infused with 10 microM MG132 (an inhibitor of NF-kappaB). TF activity was determined using a chromogenic assay in homogenates of carotid arteries and in peritoneal cells of mice. In vivo, IgG-APS increased significantly the number of white blood cells adhering to ECs (4.7 +/- 2.2) when compared to control mice (1.5 +/- 0.8), and these effects were significantly reduced when mice were pretreated with MG132 (0.8 +/- 0.2). IgG-APS increased significantly the thrombus size and MG132 inhibited that effect (93%). Treatment of the mice with IgG-APS also induced significantly increased TF function in peritoneal cells and in homogenates of carotid arteries. Pretreatment of the mice with MG132 abrogated those effects significantly. Mice injected with IgG-APS or with IgM-APS with or without the inhibitor had medium-high titers of anticardiolipin antibodies in serum at the time of the surgical procedures. The data show that prothrombotic and proinflammatory properties of IgG-APS and IgM-APS are downregulated in vivo by an NF-kappaB inhibitor. These findings may be important in designing new modalities of targeted therapies to treat thrombosis in patients with APS.

Role of p38 mitogen-activated protein kinase in antiphospholipid antibody-mediated thrombosis and endothelial cell activation.

BACKGROUND: The purpose of this study was to examine whether SB 203580, a p38 mitogen-activated protein kinase (MAPK) inhibitor, is effective in reversing the pathogenic effects of antiphospholipid antibodies. METHODS: The adhesion of THP-1 monocytes to cultured endothelial cells (EC) treated with immunoglobulin G (IgG) from a patient with antiphospholipid syndrome (IgG-APS) or control IgG (IgG-NHS) in the presence and absence of SB 203580 was examined. The size of an induced thrombus in the femoral vein, the adhesion of leukocytes to EC of cremaster muscle, tissue factor (TF) activity in carotid artery and in peritoneal macrophages, the ex vivo expression of vascular cell adhesion molecule-1 (VCAM-1) in aorta preparations and platelet aggregation were studied in mice injected with IgG-APS or control IgG-NHS and with or without SB 203580. RESULTS: SB 203580 significantly reduced the increased adhesion of THP-1 to EC in vitro, the number of leukocytes adhering to EC, the thrombus size, the TF activity in carotid arteries and in peritoneal mononuclear cells, and the expression of VCAM-1 in aorta of mice, and completely abrogated platelet aggregation induced by IgG-APS. CONCLUSION: These data suggest that targeting the p38 MAPK pathway may be valuable in designing new therapy modalities for treating thrombosis in patients with APS.